Citations

Objective: In this study, we evaluate the utility of ctDNA analysis in a large cohort of patients for whom ctDNA testing was ordered commercially with real-world application. Summary Background Data: Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for assessing post-surgical molecular residual disease (MRD) and response to treatment. Methods: A real-world data analysis was performed using commercial ctDNA testing (SignateraTM) from patients (N=795, n=5,971 plasma samples) with stage I-III colon cancer treated at multiple US institutions. The association of ctDNA detection within the MRD window, during surveillance, and the impact of ACT was correlated with patient outcomes. Results: ctDNA-positive patients during the MRD window and surveillance showed significantly shorter DFS compared to ctDNA-negative patients (hazard ratio (HR): 9.85, P<0.0001; HR: 26.91, P<0.0001). Multivariate analysis of the MRD window revealed ctDNA-positivity as the most significant factor associated with inferior DFS (adjHR: 7.7, P<0.001). MRD-positive patients who received ACT showed improved DFS compared to patients observed post-surgery (adjHR: 6.1, FDR adj P=0.0007). No ACT benefit was observed in MRD-negative patients (adj HR: 1.20, FDR adj P=0.768). On evaluating ctDNA dynamics from MRD to surveillance, patients who remained ctDNA-positive or converted from negative to positive showed a significantly inferior DFS (HR: 34.40, P<0.0001; HR: 13.65, P<0.0001) compared to persistently ctDNA-negative patients. Conclusions: Postsurgical ctDNA detection is prognostic of relapse and potentially predictive of ACT benefit in patients with resectable colon cancer, which may enable personalized surveillance, intervention, and/or trial options, ultimately improving patient outcomes.

Increases in aortic wave reflection and aortic pulsatile load are known contributors to hypertension, cardiovascular risk, and pulsatile stress to end organs. To our knowledge, this is the first study to demonstrate that evening binge alcohol consumption increases heart rate, aortic pulsatile load, and aortic augmentation index the following morning when compared with fluid control. These findings highlight the deleterious overnight cardiovascular effects of binge alcohol consumption in young adults.

Abstract Background Chimeric antigen receptor (CAR) T-cell therapy has been revolutionary in the treatment of blood cancers, but has been associated with arrhythmias such as atrial fibrillation (AF). The treatment course and cardiovascular outcomes of patients who develop new or recurrent AF after CAR-T has yet to be explored. Methods We extracted a cohort of patients who underwent CAR T-cell therapy between 2016 and 2022. The endpoint of interest was defined as the first episode of new or recurrent AF during or after CAR-T infusion. Patients with persistent or permanent AF were not counted as events. Tocilizumab use was not counted for patients who had an AF event more than 30 days after CAR-T infusion. Chart review was used to delineate patient treatments and outcomes. Survival analyses techniques were used to define risk of new or recurrent AF. Results There were 328 patients who underwent CAR T-cell therapy between 2016 and 2022, of which 41 had prior history of AF. Overall, there were 10 new and 9 recurrent AF events after CAR T-cell infusion, with a composite cumulative incidence risk of 5.8%. The majority of these events occurred within 30 days of receiving CAR-T (N=14, 73.7%). All events that occurred after 30 days were associated with significant hospitalizations unrelated to CAR-T. Rate control was the preferred method of treatment, with beta blockers being the preferred first-line therapy for both patients on and not on baseline beta blockers (Table). 2 patients were given amiodarone prophylactically prior to CAR-T infusion. Only 1 patient received cardioversion, 15 days after the AF event, but had recurrence shortly thereafter. Only 2 patients were on chronic anticoagulation, and both had history of AF prior to CAR-T. Tocilizumab was given to 9 patients (47.4%) before the onset of AF and not significantly associated to decreased risk of developing new or recurrent AF (HR 1.16, CI 0.47-2.83, P=0.75). Tocilizumab was more likely given to patients with higher cytokine release syndrome and neurotoxicity grading (Figure). There were no myocardial infarctions or strokes. Conclusion Atrial fibrillation is a rare complication of CAR T-cell therapy. Rate-control strategies remain the preferred method of treatment. Very few patients were given anticoagulation, but the incidence of subsequent stroke was negligible. More investigation will need to be undertaken to determine methods of preventing AF in the setting of CAR-T therapy.CAR-T AF Patient Case Series

Abstract Endoscopic mucosal resection (EMR) techniques for large (≥20 mm) nonpedunculated colorectal polyps (LNPCPs) have expanded with the introduction of ablation and cold EMR. This study assessed adverse events (AEs) for the newer EMR techniques, including cold EMR, compared with hot EMR. We conducted a secondary analysis of four prospective multicenter studies of consecutive patients with LNPCPs undergoing EMR from 2019 to 2024. The primary outcome was serious AEs (SAEs) with cold and hot EMR. Secondary outcomes included SAEs in the hot EMR subgroups (no ablation [hEMR], margin ablation [hEMR-m], margin and base ablation [hEMR-mb]). 1762 patients (mean age 65.8; 1890 LNPCPs) were included: 522 cold and 1368 hot EMRs (368 hEMR, 770 hEMR-m, 230 hEMR-mb). SAEs were higher with hot EMR (4.7%, 95%CI 3.6%–5.9%) vs. cold EMR (1.9%, 95%CI 0.9%–3.5%), also for the subgroups of hEMR (6.0%, 95%CI 3.8%–8.9%), hEMR-m (3.9%, 95%CI 2.6%–5.5%), and hEMR-mb (5.2%, 95%CI 2.7%–8.9%). Serious postendoscopic bleeding (PEB) was numerically higher with hot EMR (2.3%, 95%CI 1.6%–3.3%) vs. cold EMR (1.3%, 95%CI 0.5%–2.7%), also for the subgroups of hEMR (3.0%, 95%CI 1.5%–5.3%), hEMR-m (1.9%, 95%CI 1.1%–3.2%), and hEMR-mb (2.6%, 95%CI 1.0%–5.6%). Perforation, intraprocedural and post-procedural, was numerically higher with hot EMR (1.2%, 95%CI 0.7%–2.0%) vs. cold EMR (0.2%, 95%CI 0.0%–1.1%). hEMR-m and hEMR-mb with clipping had lower rates of serious and overall PEB than no clipping. Cold EMR demonstrated lower rates of SAEs, serious PEB, and perforation compared with hot EMR. Perforation and mortality occurred almost exclusively after hot EMR. Hot EMR with margin +/− base ablation did not increase SAEs compared with hot EMR without ablation.

Abstract Front-line pharmaceutical interventions for treating acute graft-versus-host disease (GVHD) are not uniformly effective and have toxic side effects. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with potent in vitro and in vivo immunosuppressive functions. Clinical translation of in vitro–generated MDSCs has been limited because of requirements for multiple, high infusion doses, the relatively low yield from peripheral blood–sourced MDSCs (PB-MDSCs), and inconsistent product quality. To circumvent these obstacles, we developed a methodology to generate MDSCs using human induced pluripotent stem cell (iPSC)–derived CD34+ cells. Compared with PB-MDSCs, iPSC-derived MDSCs (iMDSCs) shared similar morphology, phenotype, and suppressive function. We found that the CD14+ iMDSC subset possessed the highest suppressor function. In previous studies, we reported that MDSCs transferred into mice with GVHD lost suppressor function because of inflammasome activation and immature myeloid cell maturation. In striking contrast to human PB-MDSCs, we show herein that iMDSCs retained 95% of suppressor function in vitro despite exposure to lipopolysaccharide (LPS) plus adenosine triphosphate (ATP), which are stimuli that activate the inflammasome via danger-associated molecular patterns released during early posttransplant conditioning and GVHD-induced injury. In an in vivo xenogenic GVHD model with PB mononuclear cells, iMDSCs significantly increased recipient survival without loss of antileukemia effects. iMDSC RNA sequencing and gene knockdown studies revealed that the maintenance of the purine metabolizing enzyme, phosphoglycerate dehydrogenase, during LPS plus ATP treatment, was linked to iMDSC inflammasome resistance. Taken together, these findings provide a platform for translating in vitro–generated, off-the-shelf iMDSCs into the clinic for suppressing a spectrum of adverse immune responses, including GVHD.

Background Disease‐causative variants in LMNA ‐encoded lamin A/C cause a genetic cardiomyopathy characterized by atrioventricular block, atrial fibrillation, ventricular arrhythmias, and systolic dysfunction. The influence of LMNA variant type/localization on late gadolinium enhancement (LGE) patterns and clinical outcomes remains unclear. Methods Retrospective analysis of 822 genotype‐positive patients with arrhythmogenic/dilated cardiomyopathy was used to identify those with disease‐causative variants in LMNA . Data on LGE distribution and prevalence of advanced heart failure, thromboembolic and sudden cardiac death/major ventricular arrhythmia events were extracted from the electronic record and analyzed by variant type/localization. Results Among the 72/116 (62%) LMNA variant‐positive patients with cardiac magnetic resonance imaging data, LGE was observed in 40/72 (56%) cases. Most exhibited a nonischemic, midmyocardial or subepicardial pattern (73%), and 6/40 (15%) showed a unique “pseudo‐infarct” transmural pattern, predominantly affecting the apical segments. All 6 patients with this distinct LGE pattern harbored C‐terminal IgD (immunoglobulin‐like domain) variants (p.Arg471His or p.Arg541His). In patients with clinically manifest disease (76/116), those with IgD‐localizing variants had a lower prevalence of atrioventricular block (25% versus 72%, P =0.002) and atrial fibrillation (50% versus 81%, P =0.019) but higher rates of thromboembolic events (42% versus 16%, P =0.038). During a median follow‐up of 37 months, IgD variant presence independently predicted sudden cardiac death/major ventricular arrhythmia (hazard ratio, 2.391 [95% CI, 1.046–5.464]; P =0.039). Conclusions LMNA missense variants localizing to IgD present a distinct apical pseudo‐infarct LGE pattern associated with increased risk of ventricular arrhythmias and thromboembolic events but reduced atrioventricular block and atrial fibrillation. Multicenter studies are warranted to develop variant‐specific risk‐stratification strategies in cardiac laminopathy.

BACKGROUND: The Harmony transcatheter pulmonary valve (TPV) is designed to treat severe pulmonary regurgitation in the native or surgically repaired right ventricular (RV) outflow tract. Early outcomes after TPV replacement with the Harmony valve have been positive, but longer-term data are limited. METHODS: The study included patients who received a commercially available TPV22 or TPV25 device as part of the nonrandomized, prospective Native Outflow Tract Early Feasibility Study, Harmony Pivotal Trial, and Continued Access Study. Patients completed at least 3 years of follow-up, and outcomes to 5 years were reported when available. RESULTS: Eighty-nine patients were catheterized, and 86 were successfully implanted with a Harmony TPV. Median duration of follow-up was 5 (range 0–6) years in the TPV22 group and 3 (1–4) years in the TPV25 group. At 3 years, all patients with a TPV22 and 96% of those with a TPV25 had ≤mild pulmonary regurgitation. By magnetic resonance imaging, significant improvements from preimplant to 2 years were observed in RV end-diastolic volume index, RV to left ventricular end-diastolic volume ratio, and effective RV stroke volume (all P <0.001). SF-36 quality-of-life scores improved after Harmony implantation and were sustained over 3 years. Early cases of ventricular tachycardia resolved, and there were no new arrhythmias. Adverse events up to 5 years included 3 deaths unrelated to the device or procedure, 2 cases of endocarditis that were treated (1 medically, 1 transcatheter debulking of a vegetation) and resolved, 6 patients with RV outflow tract obstruction or thrombosis resulting in valve-in valve procedures, and 1 major stent fracture resulting in surgical explant. CONCLUSIONS: At 3 to 5 years, Harmony TPV replacement resulted in sustained valve competence, beneficial cardiac remodeling, and improved quality of life. Continued monitoring is needed to assess long-term outcomes and valve performance. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01762124; NCT02979587.

Objective Mechanical thrombectomy (MT) is well-established for the treatment of acute ischemic stroke (AIS) from large vessel occlusion (LVO), with growing data supporting the expansion to distal and medium vessel occlusions (DMVO). Despite successful recanalization in DMVO, certain patients still experience poor long-term clinical outcomes, prompting our study to comprehensively explore pre-MT factors influencing outcome despite excellent recanalization (final modified Thrombolysis in Cerebral Infarction [mTICI] score ≥2c). Methods We retrospectively examined data from patients who consecutively underwent MT for a primary middle cerebral artery (MCA) DMVO across 37 centers in North America, Asia, and Europe. We identified baseline clinical and imaging factors associated with poor clinical outcome (defined as a modified Rankin Scale [mRS] score of 3–6) at 3 months, despite excellent recanalization using a multivariable model. Results Between September 2017 and July 2021, 623 patients achieved mTICI > 2b and they were included in our study. Among them, 198 (32%) experienced a poor clinical outcome (mRS 3–6). Predictors of poor clinical outcome included higher age (OR 1.05 [1.03–1.07], p < 0.001), higher NIHSS at admission (OR 1.12 [1.08–1.15], p < 0.001), higher baseline mRS (OR 1.77 [0.96–3.26], p = 0.067), and diabetes (OR 1.59 [1.01–2.48], p = 0.044). Higher ASPECTS was associated with a decreased risk of poor clinical outcome (OR 0.82 [0.71–0.94], p = 0.006). Conclusion Older age, diabetes, higher baseline mRS, and NIHSS were associated with poor clinical outcome in MCA DMVO despite excellent recanalization. Conversely, a higher ASPECTS decreased the probability of such an outcome.

Background Tricuspid valve surgery is recommended for severe isolated tricuspid regurgitation (TR) if symptoms persist despite optimal medical therapy. The definition of optimal therapy for TR is unclear beyond managing underlying conditions. Diuretics are the primary treatment for volume retention in TR, but it is unknown whether a “safe diuretic dose” exists for conservative management. We sought to evaluate the association between diuretic dose and outcomes. Methods Adult patients with ≥moderate–severe isolated TR were retrospectively identified from echocardiographic reports. Clinical and echocardiographic data were extracted from electronic medical records and manually reviewed. The primary end point was all‐cause mortality. Loop diuretic doses were converted to furosemide equivalent and categorized into 4 groups: <40 mg, 40 to 79 mg, 80 to 159 mg, and ≥160 mg daily. Results Of 1302 patients (age 72±13 years, 60% female), 565 (43%) had moderate–severe TR and 737 (57%) had severe TR. Median follow‐up was 8.7 (1.4, 14.0) years. Comorbidities increased with higher diuretic doses. A linear relationship between diuretic dose and mortality was observed in spline‐curve analysis. Hazard ratios (and CIs) for mortality adjusted for age, sex, coronary disease, chronic kidney disease, mild pulmonary hypertension, and New York Heart Association III/IV symptoms were 1.21 (0.96–1.53) ( P =0.12) for <40 mg, 1.50 (1.23–1.82) ( P <0.001) for 40 to 79 mg, 1.86 (1.46–2.37) ( P <0.001) for 80 to 159 mg, and 2.90 (2.18–3.88) ( P <0.001) for ≥160 mg furosemide equivalent. Any diuretic dose was associated with significant symptoms (New York Heart Association III–IV), with more patients experiencing symptoms at higher doses. Conclusion A daily loop diuretic dose ≥40 mg furosemide equivalent is associated with increased mortality and greater symptom severity in patients with TR.